Cyclic benzimidazole derivatives useful as anti-diabetic agents

Abstract

Novel compounds of the structural formula (I) are activators of AMP-protein kinase and are useful in the treatment, prevention and suppression of diseases mediated by the AMPK-activated protein kinase. The compounds of the present invention are useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension.

What is claimed is: 
     
       1. A compound of structural formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
       X is absent or selected from:
 (1) —S—, 
 (2) —O—, 
 (3) —NH—, 
 (4) —C(O)—, 
 (5) —NHC(O)—, 
 (6) —C(O)NH—, 
 (7) —NHSO 2 —, 
 (8) —SO 2 NH—, and 
 (9) —CO 2 —, 
 
       wherein NH is unsubstituted or substituted with 1 substituent selected from: —C 1-6 alkyl, —CO 2 H, —CO 2 C 1-6 alkyl, —COC 1-6 alkyl, phenyl and —CH 2 -phenyl; 
       Y is selected from:
 (1) —CH 2 —, 
 (2) —CH 2 —CH 2 —, 
 (3) —CH 2 —CH 2 —CH 2 —, 
 (4) —CHF—, and 
 (5) —CF 2 —, 
 
       wherein each CH 2  and CHF is unsubstituted or substituted with 1 or 2 substituents selected from Rb; 
       Z is selected from:
 (1) —CO 2 H, 
 (2) —C(O)NH 2 , 
 (3) tetrazole, and 
 (4) dihydrooxadiazole, 
 
       wherein each dihydrooxadiazole and tetrazole is unsubstituted or substituted with 1, 2, or 3 substituents selected from R c ; 
       R 1  is independently selected from:
 1) —C 3-10 cycloalkyl, 
 2) —C 3-7 cycloalkyl-aryl, 
 3) —C 3-7 cycloalkyl-heteroaryl, 
 4) —C 4-10 cycloalkenyl, 
 5) —C 4-7 cycloalkenyl-aryl, 
 6) —C 4-7 cycloalkenyl-heteroaryl, 
 7) aryl, 
 8) biphenyl, 
 9) -heteroaryl, 
 10) —C 2-6 alkenyl-alkyl, 
 11) —C 2-6 alkenyl-aryl, 
 12) —C 2-6 alkenyl-heteroaryl, 
 13) —C 2-6 alkenyl-C 3-7 cycloalkyl, 
 14) —C 2-6 alkenyl-C 3-7 cycloalkenyl, 
 15) —C 2-6 alkenyl-C 2-7 cycloheteroalkyl, 
 16) —C 2-6 alkenyl-C 2-7 cycloheteroalkenyl, 
 17) —C 2-6 alkynyl-(CH 2 ) 1-3 —O-aryl, 
 18) —C 2-6 alkynyl-alkyl, 
 19) —C 2-6 alkynyl-aryl, 
 20) —C 2-6 alkynyl-heteroaryl, 
 21) —C 2-6 alkynyl-C 3-7 cycloalkyl, 
 22) —C 2-6 alkynyl-C 3-7 cycloalkenyl, 
 23) —C 2-6 alkynyl-C 2-7 cycloheteroalkyl, 
 24) —C 2-6 alkynyl-C 2-7 cycloheteroalkenyl, and 
 25) —(CH 2 ) p C(O)phenyl, 
 
       wherein each CH 2  is unsubstituted or substituted with 1 or 2 substituents selected from: halogen, CF 3 , —OH, —NH 2 , —C 1-6 alkyl, —OC 1-6 alkyl, —NHC 1-6 alkyl, and —N(C 1-6 alkyl) 2 , wherein each alkyl, alkenyl and alkynyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from: halogen, CF 3 , —OH, —NH 2 , —C 1-6 alkyl, —OC 1-6 alkyl, —NHC 1-6 alkyl, and —N(C 1-6 alkyl) 2 , and wherein each cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, phenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R a , and 
       R 2  is selected from the group consisting of: halogen, —CN, —CF 3 , —C 2-6 alkenyl and —C 2-6 alkynyl, wherein each alkenyl and alkynyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from: halogen, CF 3 , —OH, —NH 2 , —C 1-6 alkyl, —OC 1-6 alkyl, —NHC 1-6 alkyl, and —N(C 1-6 alkyl) 2 ; or R 2  represents —C 1-6 alkyl substituted with 1, 2 or 3 substituents selected from: halogen, CF 3 , —OH, —NH 2 , —OC 1-6 alkyl, —NHC 1-6 alkyl, and —N(C 1-6 alkyl) 2 ; 
       R 3  is hydrogen; 
       R 4  is hydrogen; 
       R 5  is selected from:
 (1) hydrogen, 
 (2) —C 1-6 alkyl, 
 (3) —CH 2 CO 2 H, and 
 (4) —CH 2 CO 2 C 1-6 alkyl; 
 
       each R a  is independently selected from the group consisting of:
 (1) halogen, 
 (2) oxo, 
 (3) —(CH 2 ) m OH, 
 (4) —(CH 2 ) m N(R j ) 2 , 
 (5) —(CH 2 ) m NO 2 , 
 (6) —(CH 2 ) m CN, 
 (7) —C 1-6 alkyl, 
 (8) —(CH 2 ) m CF 3 , 
 (9) —(CH 2 ) m OCF 3 , 
 (10) —OCH 2 OC 1-6 alkyl, 
 (11) —O-aryl, 
 (12) —OCH 2 -aryl, 
 (13) —(CH 2 ) m C(═N—OH)N(R j ) 2 , 
 (14) —(CH 2 ) m OC 1-6 alkyl, 
 (15) —(CH 2 ) m —O-aryl, 
 (16) —(CH 2 ) m SC 1-6 alkyl, 
 (17) —(CH 2 ) m S(O)C 1-6 alkyl, 
 (18) —(CH 2 ) m S(O) 2 C 1-6 alkyl, 
 (19) —(CH 2 ) m NHS(O) 2 C 1-6 alkyl, 
 (20) —(CH 2 ) m C(O)R f , 
 (21) —(CH 2 ) m C(O)N(R j ) 2 , 
 (22) —(CH 2 ) m N(R j )C(O)R f , 
 (23) —(CH 2 ) m N(R j )C(O)N(R j ) 2 , 
 (24) —(CH 2 ) m CO 2 H, 
 (25) —(CH 2 ) m OC(O)H, 
 (26) —(CH 2 ) m CO 2 R f , 
 (27) —(CH 2 ) m OC(O)R f , 
 (28) —(CH 2 ) m C 3-7 cycloalkyl, 
 (29) —(CH 2 ) m C 3-7 cycloalkenyl, 
 (30) —(CH 2 ) m C 2-6 cycloheteroalkyl, 
 (31) —(CH 2 ) m C 2-6 cycloheteroalkenyl, 
 (32) —(CH 2 ) m aryl, and 
 (33) —(CH 2 ) m heteroaryl, 
 
       wherein each CH 2  is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —(CH 2 ) 0-3 OH, —CN, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —C 3-7 cycloalkyl, phenyl, CH 2 phenyl, heteroaryl and CH 2 heteroaryl, and each alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —(CH 2 ) 0-3 OH, —CN, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —C 3-7 cycloalkyl, phenyl, CH 2 -phenyl, heteroaryl and CH 2 heteroaryl; 
       each R b  is independently selected from:
 (1) hydrogen, 
 (2) —C 1-6 alkyl, 
 (3) halogen, 
 (4) —OH, 
 (5) —NO 2 , 
 (6) —NH 2 , 
 (7) —NH(C 1-6 alkyl), 
 (8) —N(C 1-6 alkyl) 2 , 
 (9) —OC 1-6 alkyl, 
 (10) —CF 3 , 
 (11) —CN, 
 (12) —SO 2 C 1-6 alkyl, and 
 (13) —(CH 2 ) q CON(R e ) 2 , 
 
       wherein each CH 2  is unsubstituted or substituted with 1 or 2 halogens, and wherein each alkyl is unsubstituted or substituted with 1, 2 or 3 halogens; 
       each R c  is independently selected from:
 (1) halogen, 
 (2) oxo, 
 (3) —(CH 2 ) r OH, 
 (4) —(CH 2 ) r N(R e ) 2 , 
 (5) —(CH 2 ) r CN, 
 (6) —C 1-6 alkyl, 
 (7) —CF 3 , 
 (8) —C 1-6 alkyl-OH, 
 (9) —OCH 2 OC 1-6 alkyl, 
 (10) —(CH 2 ) r OC 1-6 alkyl, 
 (11) —OCH 2 aryl, 
 (12) —(CH 2 ) r SC 1-6 alkyl, 
 (13) —(CH 2 ) r C(O)R f , 
 (14) —(CH 2 ) r C(O)N(R e ) 2 , 
 (15) —(CH 2 ) r CO 2 H, 
 (16) —(CH 2 ) r CO 2 R f , 
 (17) —(CH 2 ) r C 3-7 cycloalkyl, 
 (18) —(CH 2 ) r C 2-6 cycloheteroalkyl, 
 (19) —(CH 2 ) r aryl, and 
 (20) —(CH 2 ) r heteroaryl, 
 
       wherein each CH 2  is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —OH, —CN, —N(R h ) 2 , —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —C 3-7 cycloalkyl and heteroaryl, and each alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN, —N(R h ) 2 , —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —C3 — 7cycloalkyl and heteroaryl; 
       each R e , R g  and R h  is independently selected from:
 (1) hydrogen, and 
 (2) C 1-6 alkyl, 
 
       wherein alkyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: —OH, oxo, halogen, C 1-6 alkyl, —OC 1-6 alkyl, —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 ; 
       each R j  is independently selected from:
 (1) hydrogen, 
 (2) C 1-6 alkyl, 
 (3) C 3-6 cycloalkyl, 
 (4) —C(O)R i , and 
 (5) —SO 2 R i , 
 
       wherein alkyl and cycloalkyl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: —OH, oxo, halogen, C 1-6 alkyl, —OC 1-6 alkyl, —NH 2 , —NH(C 1-6 alkyl), and —N(C 1-6 alkyl) 2 ; 
       each R f  and R i  is independently selected from:
 (1) C 1-6 alkyl, 
 (2) C 4-7 cycloalkyl, 
 (3) C 4-7 cycloalkenyl, 
 (4) C 3-7 cycloheteroalkyl, 
 (5) C 3-7 cycloheteroalkenyl, 
 (6) aryl, and 
 (7) heteroaryl, 
 
       wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN, —NH 2 , —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, —C 3-7 cycloalkyl, and heteroaryl; 
       n is 0, 1, 2, 3 or 4; 
       m is 0, 1, 2, 3 or 4; 
       p is 1; 
       q is 0, 1, 2, 3 or 4; and 
       r is 0, 1 or 2. 
     
     
       2. The compound according to  claim 1 , wherein X is absent or selected from: —S— and —O—, or a pharmaceutically acceptable salt thereof. 
     
     
       3. The compound according to  claim 2 , wherein X is selected from: —S— and —O—, or a pharmaceutically acceptable salt thereof. 
     
     
       4. The compound according to  claim 3 , wherein Y is selected from: —CH 2 — and —CH 2 —CH 2 —, wherein each —CH 2  is unsubstituted or substituted with 1 or 2 substituents selected from Rb; or a pharmaceutically acceptable salt thereof. 
     
     
       5. The compound according to  claim 4 , wherein Y is —CH 2 —, wherein CH 2  is unsubstituted or substituted with 1 or 2 substituents selected from R b ; or a pharmaceutically acceptable salt thereof. 
     
     
       6. The compound according to  claim 5 , wherein Z is —CO 2 H; or a pharmaceutically acceptable salt thereof. 
     
     
       7. The compound according to  claim 1 , wherein R 5  is hydrogen; or a pharmaceutically acceptable salt thereof. 
     
     
       8. The compound according to  claim 7 , wherein 
       R 1  is selected from:
 1) aryl, 
 2) biphenyl, 
 3) heteroaryl, 
 4) —C 2-6 alkynyl-(CH 2 ) 1-3 —O-aryl, 
 5) —C 2-6 alkynyl-aryl, 
 6) —C 2-6 alkynyl-heteroaryl, 
 7) —C 2-6 alkynyl-C 3-7 cycloalkyl, 
 8) —C 2-6 alkynyl-C 2-7 cycloheteroalkyl, and 
 9) —(CH 2 ) p C(O)phenyl, 
 
       wherein each CH 2  is unsubstituted or substituted with 1 or 2 substituents selected from: halogen, CF 3 , —OH, —NH 2 , —C 1-6 alkyl, —OC 1-6 alkyl, —NHC 1-6 alkyl, and —N(C 1-6 alkyl) 2 , wherein each alkynyl is unsubstituted or substituted with 1 or 2 substituents selected from: halogen, CF 3 , —OH, —NH 2 , —C 1-6 alkyl, —OC 1-6 alkyl, —NHC 1-6 alkyl, and —N(C 1-6 alkyl) 2 , and wherein each cycloalkyl, cycloheteroalkyl, phenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from R a , and 
       R 2  is halogen; and 
       p is 1; 
       or a pharmaceutically acceptable salt thereof. 
     
     
       9. The compound according to  claim 8 , wherein each R a  is independently selected from the group consisting of:
 (1) halogen, 
 (2) —(CH 2 ) m OH, 
 (3) —N(R j ) 2 , 
 (4) —NO 2 , 
 (5) —CN, 
 (6) —C 1-6 alkyl, 
 (7) —CF 3 , 
 (8) —O-aryl, 
 (9) —OCH 2 -aryl, 
 (10) —OC 1-6 alkyl, 
 (11) —SC 1-6 alkyl, 
 (12) —S(O)C 1-6 alkyl, 
 (13) —S(O) 2 C 1-6 alkyl, 
 (14) —NHS(O) 2 C 1-6 alkyl, 
 (15) —C(O)N(R j ) 2 , 
 (16) —(CH 2 ) m N(R j )C(O)R f , 
 (17) —N(R j )C(O)N(R j ) 2 , 
 (18) —CO 2 H, 
 (19) —C 2-6 cycloheteroalkyl, 
 (20) aryl, and 
 (21) heteroaryl, 
 
       wherein each CH 2  is unsubstituted or substituted with 1 or 2 substituents selected from: oxo, —(CH 2 ) 0-3 OH, —CN, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl, and wherein alkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 substituents selected from: oxo, —(CH 2 ) 0-3 OH, —CN, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl; or a pharmaceutically acceptable salt thereof. 
     
     
       10. The compound according to  claim 1  of structural formula Ib: 
       
         
           
           
               
               
           
         
       
       wherein: 
       R 1  is selected from:
 (1) phenyl, 
 (2) biphenyl, 
 (3) heteroaryl, and 
 (4) —C 2 alkynyl-phenyl, 
 
       wherein each phenyl and heteroaryl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from R a ; 
       R 2  is halogen; 
       R 3 , R 4  and R 5  are hydrogen; 
       X is selected from: —S— and —O—; 
       Z is —CO 2 H; 
       each R a  is independently selected from the group consisting of:
 (1) —(CH 2 ) m OH, 
 (2) —C 1-6 alkyl, 
 (3) phenyl, and 
 (4) heteroaryl, 
 
       wherein each alkyl, phenyl and heteroaryl is unsubstituted or substituted with 1, 2 or 3 substituents selected from: oxo, —(CH 2 ) 0-3 OH, —CN, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —C 1-6 alkyl, —OC 1-6 alkyl, halogen, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —CO 2 C 1-6 alkyl; 
       each R b  is independently selected from: hydrogen, and —C 1-6 alkyl, wherein each alkyl is unsubstituted or substituted with 1, 2 or 3 halogens; and 
       s is 0, 1 or 2; 
       or a pharmaceutically acceptable salt thereof. 
     
     
       11. The compound according to  claim 10  selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       12. A composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       13. A composition comprising a compound according to  claim 1 , a compound selected from simvastatin, ezetimibe, taranabant and sitagliptin; and a pharmaceutically acceptable carrier.